Compounds
The invention relates to compounds or pharmaceutically acceptable salts thereof, compositions containing them, including combinations with at least one additional therapeutic agent, and their use in therapy, for example in the treatment of mycobacterial infections or in the treatment of diseases caused by a mycobacterium, such as tuberculosis.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R 4 is
R 1 is methoxy, ethoxy, pyrazolyl, substituted pyrazolyl or —NHMe;
R 2 and R 2A are each independently hydrogen or fluorine;
R 3 and R 3A are each independently hydrogen or methyl;
X is CH or N; and
n is 1 or 2.
2 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein n is 1.
3 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein n is 2.
4 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 and R 3A are each hydrogen.
5 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 and R 2A are each fluorine.
6 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is ethoxy.
7 . The compound or pharmaceutically acceptable salt thereof according to claim 6 , wherein the compound is selected from the group consisting of:
8 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is methoxy.
9 . The compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein the compound is selected from the group consisting of:
10 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is pyrazolyl or 4-ethoxy-1H-pyrazol-1-yl.
11 . The compound or pharmaceutically acceptable salt thereof according to claim 10 , wherein the compound is selected from the group consisting of:
12 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is —NHMe.
13 . The compound or pharmaceutically acceptable salt thereof according to claim 12 , wherein the compound is
14 . A compound selected from the group consisting of:
2-amino-4-ethoxy-6-[(1R,2S)-2-hydroxycyclohexyl]-7H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-4-ethoxy-6-((1R,2S)-2-hydroxycycloheptyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-6-((1S,6S)-2,2-difluoro-6-hydroxycyclohexyl)-4-ethoxy-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-6-((1R,2S)-2-hydroxycycloheptyl)-4-methoxy-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-6-((1S,6S)-2,2-difluoro-6-hydroxycyclohexyl)-4-methoxy-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-6-((1S,7S)-2,2-difluoro-7-hydroxycycloheptyl)-4-methoxy-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-6-((1S,7S)-2,2-difluoro-7-hydroxycycloheptyl)-4-(methylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-6-((1S,7S)-2,2-difluoro-7-hydroxycycloheptyl)-4-(1H-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-6-((1S,2R)-2-hydroxycycloheptyl)-4-methoxy-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-4-ethoxy-6-((1S,2R)-2-hydroxycycloheptyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;
2-amino-4-(4-ethoxy-1H-pyrazol-1-yl)-6-((1R,2S)-2-hydroxycyclohexyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one; and
(S)-2-amino-6-(2,2-difluorocyclohexyl)-4-(4-ethoxy-1H-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one.
15 . A compound which is
or a pharmaceutically acceptable salt thereof.
16 . A pharmaceutical composition comprising (a) the compound or pharmaceutically acceptable salt thereof according to claim 1 , and (b) a pharmaceutically acceptable excipient.
17 . A kit comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 , and instructions for administering to a human in need thereof.
18 . A method of treating a mycobacterial infection in a human in need thereof, the method comprising administering to said human a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as defined in of claim 1 .
19 . A method of treating a disease caused by infection with a mycobacterium in a human in need thereof, the method comprising administering to said human a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as defined in claim 1 .
20 . (canceled)
21 . (canceled)
22 . The method according to claim 18 , wherein the mycobacterial infection is a Mycobacterium tuberculosis infection.
23 . (canceled)
24 . The method according to claim 19 , wherein the disease is tuberculosis.
25 . (canceled)
26 . A combination of (a) a compound or pharmaceutically acceptable according to claim 1 ; and (b) at least one other anti-mycobacterial agent.
27 . The combination according to claim 26 , wherein the at least one other anti-mycobacterial agent is an anti-tuberculosis agent.
28 . The combination according to claim 27 , wherein the anti-tuberculosis agent is selected from the group consisting of: isoniazid, rifampin, pyrazinamide, ethambutol, rifapentine, clofazimine, ethionamide, prothionamide, isoxyl, thiacetazone, rifabutin, 4-aminosalicylic acid, cycloserine, spectinamide 1810, a fluoroquinolone such as moxifloxacin, gatifloxacin or levofloxacin; a diarylquinoline such as bedaquiline or TBAJ-587 or TBAJ-876; nitroimidazo-oxazine PA-824, delamanid, an oxazolidinone such as linezolid, tedizolid, radezolid, sutezolid (PNU-100480), posizolid, Delpazolid or TBI-223; SPR720, EMB analogue SQ109, OPC-167832, telacebec, spectinamide 1810, GSK3036656, GSK2556286, GSK3211830, GSK3778839, GSK3729098, GSK3653038, a benzothiazinone such as BTZ043 or macozinone; an azaindole such as TBA-7371, a dihyrdocarbostyril derivative such as OPC-167832; a dinitrobenzamide, a beta-lactam such as meropenem, faropenem, ertapenem, tebipenem, sanfetrinem; a beta-lactam combination such as amoxicillin-clavulanate, or an aminoglycoside such as kanamycin, amikacin, capreomycin or streptomycin.
29 . The combination according to claim 27 , wherein the anti-tuberculosis agent is selected from the group consisting of: isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin, rifapentine, clofazimine, ethionamide, prothionamide, isoxyl, thiacetazone, bedaquiline, TBAJ-587, nitroimidazo-oxazine PA-824, delamanid, linezolid, tedizolid, radezolid, sutezolid, posizolid, TBI-223, EMB analogue SQ109, OPC-167832, GSK3036656, GSK2556286, GSK3211830, BTZ043, PBTZ169, TBA-7371, a dinitrobenzamide, a beta-lactam, meropenem, faropenem, ertapenem, tebipenem, beta-lactam combinations, and amoxicillin-clavulanate.
30 . The combination according to claim 26 -, further comprising an antiviral agent.
31 . The combination according to claim 30 , wherein the antiviral agent is an antiretroviral agent selected from the group consisting of: abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, indinavir, slatravir, lamivudine, lopinavir, maraviroc, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, and zidovudine.